The long-term goals of this laboratory are to broaden our understanding of the organization and function of endogenous pain suppression systems that modulate spinal nociceptive transmission by using anatomical, pharmacological and physiological techniques. Elucidating the basic mechanisms of nociceptive processing will aid in the development of more effective and selective analgesic agents to treat pain. Aim 1 is designed to investigate the mechanisms and specificities of action of selective alpha adrenoceptor agonists on physiologically and anatomically characterize neurons in laminae I and II of the spinal cord dorsal horn. Aim 2 will investigate the contribution of endogenous descending noradrenergic systems to the modulation of laminae I and II dorsal horn neuronal activity produced by electrical stimulation in the nucleus raphe magnus and the nucleus locus coeruleus. Aim 3 will examine the density and distribution of noradrenergic varicosities on intracellularly labeled laminae I and II dorsal horn neurons. Superficial dorsal horn neurons receive input from nociceptive-specific primary afferents; thus, they particularly are relevant to spinal nociceptive processing. In Aim 4, the immunohistochemically localized c-fos oncogene will be utilized as a marker for non-specific neuronal activity, to determine which noradrenergic brainstem nuclei contribute to nucleus raphe magnus stimulation-produced inhibition of spinal nociceptive transmission. How descending inhibitory systems function as an integrated system within the brainstem to modulate spinal nociceptive processing is poorly understood; the proposed experiments will begin to explore this issue. The clinical potential of alpha adrenergic agonists as analgesic agents already has been recognized. Clonidine, an alpha2 adrenoceptor agonist, produces an analgesia when administered intrathecally to morphine-tolerant cancer patients. The importance of this finding to the treatment of chronic pain is readily apparent since few pharmacologic alternatives currently are available to treat pain in the opioid-tolerant patient. Achieving a better understanding of how exogenously applied alpha adrenoceptor agonists, and endogenous descending noradrenergic systems modulate spinal nociceptive transmission is of potential therapeutic importance to the development of more selective and effective analgesic agents.